A Caltech Library Service

Computational modelling of T-cell formation kinetics: output regulated by initial proliferation-linked deferral of developmental competence

Manesso, Erica and Chickarmane, Vijay and Kueh, Hao Yuan and Rothenberg, Ellen V. and Peterson, Carsten (2013) Computational modelling of T-cell formation kinetics: output regulated by initial proliferation-linked deferral of developmental competence. Journal of the Royal Society Interface, 10 (78). Art. No. 20120774. ISSN 1742-5689. PMCID PMC3565808. doi:10.1098/rsif.2012.0774.

PDF (Data Supplement and Figures ) - Supplemental Material
See Usage Policy.


Use this Persistent URL to link to this item:


Bone-marrow-derived progenitors must continually enter the thymus of an adult mouse to sustain T-cell homeostasis, yet only a few input cells per day are sufficient to support a yield of 5 × 10^7 immature T-cells per day and an eventual output of 1–2 × 10^6 mature cells per day. While substantial progress has been made to delineate the developmental pathway of T-cell lineage commitment, still little is known about the relationship between differentiation competence and the remarkable expansion of the earliest (DN1 stage) T-cell progenitors. To address this question, we developed computational models where the probability to progress to the next stage (DN2) is related to division number. To satisfy differentiation kinetics and overall cell yield data, our models require that adult DN1 cells divide multiple times before becoming competent to progress into DN2 stage. Our findings were subsequently tested by in vitro experiments, where putative early and later-stage DN1 progenitors from the thymus were purified and their progression into DN2 was measured. These experiments showed that the two DN1 sub-populations divided with similar rates, but progressed to the DN2 stage with different rates, thus providing experimental evidence that DN1 cells increase their commitment probability in a cell-intrinsic manner as they undergo cell division. Proliferation-linked shifts in eligibility of DN1 cells to undergo specification thus control kinetics of T-cell generation.

Item Type:Article
Related URLs:
URLURL TypeDescription DOIArticle CentralArticle
Kueh, Hao Yuan0000-0001-6272-6673
Rothenberg, Ellen V.0000-0002-3901-347X
Additional Information:© 2012 The Author(s). Published by the Royal Society. Received: 25 September 2012; Accepted: 24 October 2012. Published online November 14, 2012. This work was supported by the Swedish Research Council (Vr 621-2008-3074), the Swedish Foundation for Strategic Research (A3 04 159p), the United States Public Health Service (NIH grant no. AI095943 (EVR)). E.M. was also supported by the Landshovding Per Westling Foundation, H.Y.K. by an Irvington Institute Fellowship of the Cancer Research Institute, and E.V.R. by the Albert Billings Ruddock Professorship of Biology. V.C. would like to acknowledge Prof. Elliot Meyerowitz for support. We thank Mary Yui and Ni Feng at Caltech for advice and assistance with thymocyte experiments. We also thank Diana Perez from the Caltech Cell Sorting Facility for cell sorting, and Rob Butler and Scott Washburn for mouse care as well as colleagues in Computational Biology at Lund University for useful discussions.
Funding AgencyGrant Number
Swedish Research CouncilVr 621-2008-3074
Swedish Foundation for Strategic ResearchA3 04 159p
Landshovding Per Westling FoundationUNSPECIFIED
Cancer Research Institute Irvington Institute FellowshipUNSPECIFIED
Albert Billings Ruddock Professorship of BiologyUNSPECIFIED
Issue or Number:78
PubMed Central ID:PMC3565808
Record Number:CaltechAUTHORS:20130107-112150916
Persistent URL:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:36205
Deposited By: Tony Diaz
Deposited On:07 Jan 2013 23:00
Last Modified:09 Nov 2021 23:20

Repository Staff Only: item control page